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1 1 2 the Novel Leishmanial Copper P-Type Atpase Plays a Vital Role In bioRxiv preprint doi: https://doi.org/10.1101/2021.01.01.425060; this version posted January 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 2 3 The novel leishmanial Copper P-type ATPase plays a vital role in intracellular parasite survival 4 5 Rupam Paul#1, Sourav Banerjee#1, Samarpita Sen1, Pratiksha Dubey2, Anand K Bachhawat2, 6 Rupak Datta$1, Arnab Gupta$1 7 8 1Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 9 West Bengal -741246, India 10 2Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Knowledge 11 city, Sector 81, Manauli, PO, Sahibzada Ajit Singh Nagar, Punjab-140306, India 12 13 # contributed equally 14 $Correspondence to 15 Arnab Gupta: [email protected]; Rupak Datta: [email protected] 16 17 18 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.01.425060; this version posted January 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 19 Abstract 20 Copper is essential for all life forms; however in excess it is extremely toxic. Toxic properties of copper are 21 utilized by hosts against various pathogenic invasions. Leishmania, in its both free-living and intracellular 22 forms was found to exhibit appreciable tolerance towards copper-stress. To determine the mechanism of 23 copper-stress evasion employed by Leishmania we identified and characterized the hitherto unknown Copper- 24 ATPase in Leishmania major and determined its role in parasite’s survival in host macrophage cells. L. major 25 Cu-ATPase, LmATP7, exhibits high homology with its orthologues at multiple conserved motifs. In 26 promastigotes, LmATP7 localized to the plasma membrane with a fraction in intracellular puncta. Upon 27 copper treatment, LmATP7 expression increases few folds. LmATP7 is capable of complementing copper 28 transport in Cu-ATPase-Δ yeast strain. Promastigotes overexpressing LmATP7 exhibits higher survival upon 29 copper stress indicating efficacious copper export compared to wild type parasites. We explored macrophage- 30 Leishmanial interaction with respect to copper stress subjected by the host upon parasite and the parasite’s 31 reciprocating response thereon to evade the stress. The Copper-P-type-ATPases ATP7A/7B serves as major 32 copper exporter in eukaryotes that maintain cellular copper levels. We found that Leishmania infection, 33 triggers ATP7A upregulation in macrophages. Additionally, as part of host response, ATP7A traffics from 34 trans-Golgi network and transports copper to the endosomal and endolysosomal compartments harbouring the 35 Leishmania amastigotes. Finally, we show LmATP7 overexpression in this parasite, increased amastigote 36 survivability within infected macrophages, establishing its role in combating host-induced copper stress. 37 38 39 Keywords: ATP7, Leishmania, Copper, Cu-ATPase, lysosome, ATP7A, host-pathogen interaction 40 41 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.01.425060; this version posted January 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 42 Introduction 43 Leishmania is a digenetic protozoan belonging to the trypanosomatid group that alternates between sandfly 44 vector and mammalian hosts. They are known to cause a wide spectrum of a tropical human diseases 45 collectively known as leishmaniasis. Severity of the disease depends on the Leishmania species and is 46 manifested by a range of symptoms that varies from disfiguring skin lesions to life-threatening infection of 47 the visceral organs.1 With more than a million new cases and 20,000-30,000 deaths every year, 12 million 48 people are currently affected from about 100 endemic countries imposing a significant threat to the global 49 healthcare system.2,3 Once the flagellated promastigote form of Leishmania enter mammalian host via sand 50 fly bite, they are rapidly phagocytosed by macrophages.4 Phagocytosis occurs either directly or by engulfment 51 of the parasite-harbouring apoptotic neutrophils followed by transformation from promastigotes into non- 52 flagellated amastigotes in the phagolysosome. Within the acidic phagolysosomes, they continue to proliferate 53 until the cell bursts, leading to the spread of the infection.5 Inside this compartment Leishmania has to 54 withstand a variety of host-induced stress factors including free radicals, lysosomal hydrolases and low pH.6,7 55 They are not only equipped to defend against such harsh environment but they can also manipulate host gene 56 expression to their benefit.8,9,10 Unavailability of a vaccine along with increasing resistance of the existing 57 drugs makes it even more important to understand Leishmania physiology and the molecular mechanisms 58 which allow them to thrive inside the host.11,12 59 Copper is an essential micronutrient for biological system. Several enzymes, involved in catalysing 60 biochemical processes, utilize the ability of copper to cycle between cuprous and cupric states. Shuttling 61 between Cu(II) and Cu(I) states can lead to oxidative damage of cells via Fenton like reaction when free 62 copper is available.13 Organisms have evolved mechanisms where several proteins are involved in tightly 63 regulating the bioavailability of copper.14 Copper homeostasis, which includes regulating its transport and 64 intercellular distribution, is crucial as excess copper can be detrimental. Copper binding proteins, chaperones, 65 transporters keep intracellular free copper at a very low level in the order of 10−18M.15 66 Various studies have shown that copper plays a key role in host-pathogen interaction. Copper-deficient hosts 67 are more susceptible to several pathogens that include prokaryotes like Salmonella typhimurium, Pasteurella 68 hemolytica and eukaryotes like Candida albicans, Trypanosoma lewisi.16,17,18,19 The bactericidal activity of 69 macrophages and neutrophils is also impaired upon copper deficiency.20,21 Similarly, copper channelization 70 to the phagosomal compartment of macrophage during Mycobacterium avium and E.coli infection indicated 71 how hosts tend to utilize copper to fight off intracellular pathogens.22,23 E.coli mutant with a defective copper 72 exporting system showed significantly more susceptibility to copper mediated killing within macrophage.23 73 The P-type Cu-ATPases are involved in removing excess copper from the cell and are one of the key players 74 in maintaining copper homeostasis. In bacteria, CopA and CopB are the Cu-ATPases that carry out this 75 role.24,25 There is a single Cu-ATPase in lower eukaryotes (non-chordates) referred to as Ccc2p in yeast 76 Saccharomyeces cerevisiae or ATP7 in Drosophila melanogaster or simply Cu-ATPase.26 With increased 77 complexity, ATP7A and ATP7B are branched out of ATP7 in higher eukaryotes.27 In the present study, we 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.01.425060; this version posted January 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 78 have cloned and functionally characterized a novel copper transporting ATPase (LmATP7) of Leishmania 79 major (LmATP7) and determined its role in leishmanial survivability in host macrophage. Our study shows 80 for the first time the physiological function of a full-length Cu-ATPase belonging to the kinetoplastida order. 81 Additionally, our study reveals the protective role of LmATP7 in free living promastigotes in copper stress. 82 Further, we also establish that intracellular amastigotes combat host-induced copper stress in lysosomes using 83 LmATP7 that plays a key role in determining its pathogenicity and successful manifestation of infection. 84 85 MATERIALS AND METHODS 86 87 Reagents were purchased from Sigma-Aldrich (St. Louis, Missouri, United States) unless mentioned 88 specifically. Primers were obtained from GCC biotech (West Bengal, India) and their sequence details are 89 provided in Table S1. 90 91 Plasmids and antibodies 92 Leishmania expression vector (pXG-GFP+) was a generous gift from Dr. Stephen M. Beverley (Washington 93 University Medical School, St. Louis). Mammalian expression vector (pcDNA3.1+) was a kind gift from Dr. 94 Partho Sarothi Ray (IISER Kolkata). 95 Following are the antibodies were used for experiments: rabbit anti-ATP7A (ab 125137, Abcam, Cambridge, 96 United Kingdom), goat anti-Rab11 (# sc- 6565, Santa Cruz Biotechnology, Dallas, Texas, United States), 97 mouse anti-Rab7 (# sc-376362, Santa Cruz Biotechnology, Dallas, Texas, United States), mouse anti-Lamp1 98 (DSHB: # H4A3, Iowa City, IA, United States), mouse anti-Lamp2 (DSHB: # H4B4, Iowa City, IA, United 99 States), mouse anti-golgin97 (# A21270, Invitrogen, Carlsbad, California, United States), rabbit anti-calnexin 100 (ab22595, Abcam, Cambridge, United Kingdom), rabbit anti-GFP (# BB-AB0065, Biobharati, Kolkata, 101 India), rabbit anti-GAPDH (# BB-AB0060, BioBharati, Kolkata, India), donkey anti-rabbit IgG (H+L) Alexa 102 Fluor 488 (# A-21206, Invitrogen, Carlsbad, California, United States), donkey anti-goat IgG (H+L) Alexa 103 Fluor 564 (# A-11057, Invitrogen, Carlsbad, California, United States), goat anti-rabbit
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